I would now like to hand the conference over to Mr. Stewart Holmstrom, Director of Corporate Communications. Please go ahead.
Hello, everybody. My name is Stewart Holmstrom, Director of Corporate Communications at Telix. We're very pleased to welcome you today to our educational webinar to present on unlocking the potential of PSMA therapy and Telix's next generation portfolio approach. We can just move to the next slide, please. I ask you to take a moment to look at our disclaimer. Next slide, please. I'm very pleased to introduce today's speakers. Dr. David Cade, Group Chief Medical Officer at Telix, will present on Telix's PSMA targeting therapeutic portfolio.
I'm delighted to welcome our guest speaker, Professor Louise Emmett, Director of Theranostics and Nuclear Medicine at St Vincent's Hospital Sydney, a Conjoint Professor of Medicine at the University of New South Wales, and Clinical Research Leader at Garvan Institute of Medical Research, and also the Principal Investigator on the OPTIMAL-PSMA trial that she will present today, along with case studies and perspectives based on her experience with TLX597-Tx. Following the presentation, Dr. Cade will take questions via the conference line and webcast Q&A function. Professor Emmett, who has been very generous with her time already whilst presenting in Europe, will be available afterwards to respond to questions via email. With that, I'd like to hand over to David.
Next slide, please. Well, thank you, Stewart. Today, together with Professor Louise Emmett, who's one of the globally recognized pioneers in the development of radiopharmaceutical therapies for prostate cancer, I'm hoping that we'll be able to enable you to gain from our discussion a useful understanding of three important themes. The first of those is, we'll briefly discuss the current first-generation small molecule radioligand therapies and where in the treatment cascade they've established themselves for advanced prostate cancer. Secondly, we'll also discuss some of the challenges that have emerged in applying first-generation small molecule agents earlier in prostate cancer, where patients tend to be fitter and healthier. Why Telix is taking a portfolio approach based on very distinct mechanisms of action.
With TLX 591-Tx, which is a radioantibody-drug conjugate, being developed for advanced metastatic castration-resistant prostate cancer in the ongoing phase III ProstACT Global trial. With TLX 597-Tx, which we haven't really talked a lot about previously. This is a highly targeted second-generation small molecule radioligand, which has demonstrated a favorable dosimetry profile with a very minimal salivary gland and kidney dose, but a very high tumor dose, which really makes it uniquely positioned for use in earlier metastatic hormone-sensitive prostate cancer.
Thirdly, I'm looking forward to Professor Emmett, who will discuss her St Vincent's Hospital Sydney group's rapidly growing experience with TLX597-Tx, which Professor Emmett and her team are studying in the OPTIMAL-PSMA randomized phase II trial, which Professor Emmett presented very recently at the IPCS Congress in Lugano, Switzerland. If you go to the next slide, please. I think this slide really very nicely summarizes on the left-hand side there, how we would typically treat prostate cancer once it's broken free from the prostate gland, and it's become metastatic. What you can see is that for early metastatic hormone-sensitive prostate cancer, at the start of the disease journey, we would typically use androgen deprivation therapy to block testosterone.
Or we'll use the newer androgen receptor pathway inhibitors, or we may use a taxane chemotherapy, especially if the patient has high volume metastatic disease. What invariably happens is the prostate cancer learns how to progress despite the testosterone tap having been turned off, which is what we call metastatic castration-resistant prostate cancer. We see that PSMA-617, which is Novartis' agent Pluvicto, is appropriately established for advanced metastatic castration-resistant cancer over on the right. This was established three or four years ago when the VISION trial showed a four-month extension in overall survival with PSMA-617 when compared to conventional standard of care. From here, of course, you know, a very logical next development of such an agent is to undertake trials in earlier disease settings, which is what the PSMAddition trial sought to do.
What PSMAddition also showed is that there are emerging concerns when we try to treat earlier, healthier patients. The two main concerns really could be summarized as the radiation dose to the salivary glands that tends to lead to dry mouth that then degrades patients' quality of life. As well as the radiation dose to the kidneys, which may lead to long-term kidney injury. In other words, we're probably over-treating these patients with a first-generation radioligand therapy, whereas what we really need is a second-generation agent that exhibits a very low dose to any of the normal tissues if we're truly going to be able to deploy radioligand therapy widely in early mHSPC. If you go to the next slide.
I think this really does nicely summarize those points that were made at the ESMO Congress in Berlin last October, where Dr. Tagawa from Weill Cornell, he presented the interim data from PSMAddition, and Dr. Azad from Peter MacCallum Cancer Centre in Melbourne was the discussant. He critically discussed the results from PSMAddition and the take-home messages that we in the audience should take away for our clinical practice. What he concluded were really four key take-home messages. The first of those was that PSMAddition is the first randomized phase III trial demonstrating efficacy of radioligand therapy in mHSPC. Ultimately, the progression-free survival benefit will probably lead to regulatory approval in multiple jurisdictions.
To date, to date, there's been no improvement in overall survival really shown, and to date, lower quality of life has been exhibited with PSMA-617 in this disease setting. That's a very important point. Secondly, he reminded us, as we sometimes forget that, he reminded us that the goal of any cancer treatment is to make patients not just live longer, but also live better. The discussant's view was that this was not achieved in PSMAddition. Thirdly, he indicated that he wouldn't currently recommend the widespread use of PSMA-617 in mHSPC at this stage.
The final point he made, which is very important, was that to deliver the best outcomes in mHSPC, it's gonna take a really patient-centric approach focused on avoiding over-treatment while minimizing the impact on quality of life and minimizing those late toxicities. If you go to the next slide, please. If we took all that we've learned from the last few years' experience gained with first-generation small molecules and say we were to draw up a wish list, if you will, of those characteristics that a second-generation radioligand therapy would need to succeed, these can be summarized, I think, very simply.
Firstly, we would absolutely demand a very low radiation dose to that organ that's responsible for clearing the radioactive drug from the body, which for small molecules is typically the kidney, or we'd prefer the clearance organ to be the liver, which is an organ that is actually quite forgiving of radiation delivered to it. Secondly, we'd also demand, you know, a very low radiation dose to the exocrine glands, you know, primarily the salivary and the tear glands. Thirdly, we'd also demand a higher and more prolonged tumor retention, especially given the relatively short retention time that characterizes first-generation agents.
Fourthly, we'd wanna be able to apply a very patient-centered approach with both dose intensification, which is dialing up the amount of activity that we administer, and adaptive dosing, which is administering only when the patient needs it to simultaneously improve both disease control and quality of life, which Professor Emmett's gonna discuss. You know, she's gonna discuss these concepts in a bit more detail shortly. Finally, we'd ask for compatibility with alpha isotopes like Actinium and lead. Next slide, please. With those attributes in mind, let's now move to TLX-597-Tx or lutetium DOTA-HYNIC-panPSMA to give it its full name.
What was evident right from the very early phase I trial that was done by Professor Omar's group was that TLX597-Tx is a highly targeted small molecule agent with a dosimetry profile that exhibits a minimal kidney and salivary gland dose while achieving some very significant PSMA, PSA reductions in heavily pre-treated patients. You can see this in these two patients from Professor Omar's study on the left-hand side there that he reported at the European Nuclear Medicine meeting just late last year.
Now, today, Professor Emmett's more recent randomized phase II trial, known as OPTIMAL-PSMA, that's about to complete patient enrollment, has further demonstrated the very highly targeted behavior of TLX597-Tx, again, with really minimal uptake in the kidneys and the salivary glands, while in Professor Emmett's study, additionally confirming very high radiation dose being delivered to the tumors, which is exactly what we want. Now, if you think about these properties a little more deeply, they uniquely position the TLX597-Tx agent for the important developmental objectives of, number one, dose intensification and adaptive dosing, which Professor Emmett's gonna talk about shortly, as well as use in earlier metastatic hormone-sensitive prostate cancer. Professor Emmett will discuss this concept in a bit more detail as well. Next slide, please.
I think this is my last slide, and I think it really, you know, is articulate in its simplicity. While I won't spend too much time here, this summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are tailored to both the disease state itself as well as the condition of the patient.
The way I would summarize it is TLX591-Tx, which employs the radioantibody drug conjugate mechanism of action, utilizes an antibody-targeting vector to deliver that therapeutic payload, which enables long tumor retention with limited radiation to the healthy organs, as we would want, and that the short two-dose regimen with two fractions two weeks apart is primarily intended to allow this agent to be combined with the other standard of care agents that the patient's also going to be receiving in the mCRPC setting. That's the intent of ProstACT Global that many in the audience would be familiar with.
Whereas, on the other hand, there's a very significant opportunity in mHSPC for TLX597-Tx due to its potentially best-in-class dosimetry profile that makes it uniquely suitable for earlier use in mHSPC, as well as for dose intensification to achieve those further efficacy gains. Hopefully that sets the scene, nicely and clearly. I think it's time I pass the mic to Professor Emmett, who's going to discuss some of what I believe to be really groundbreaking work that she and her group has been doing at St. Vincent's here in Sydney. With that, I'd like to pass to you, Professor Emmett.
Thanks, David. It's a great pleasure to be here and to be able to discuss OPTIMAL-PSMA, which we've been beavering away at now for about nine months. Just next slide. OPTIMAL-PSMA is a randomized phase II trial. Well, it's about dose intensification compared to standard of care dosing. It really originated from this slight frustration, I guess, of the fact that we're dosing six doses six-weekly. Most doses are 7.4 GBq . We based that dosing on external beam dose constraints to the kidney. We haven't based it on efficacy. We've done a number of randomized phase III trials at the moment now where we haven't had a lot of significant kidney dose, but we've struggled with overall survival.
We have shorter, progression-free survival than I would like to see with PSMA radioligand therapy. The question is: Are we actually optimally dosing? OPTIMAL-PSMA is about evaluating the dosing interval and whether we should do short intensified dosing right up front to attack the cancer cells when they're most vulnerable. Then have maintenance, or I call it mowing the lawn, a little bit, you know, for later. We're doing six doses on each arm over six weeks, but we're dose intensifying upfront in just one of the doses. It was very nice that we were able to really do some work on lutetium-PSMA-597 before the trial started. We safety lead in with the trial and looked at the dosimetry.
Dosimetry is a big part of the trial and we're doing a lot of translational work as well. Perhaps we can just look at the next slide and just have a look at the dosimetry. This is dosimetry that's been derived from the safety lead in, first 12 patients of the trial. Single, single injection, first dose of these patients, they had three time point dosimetry with the TLX597-Tx. Just compared to previous publications of PSMA-617 and PSMA I&T. What we see with the dosimetry, and it's been done twice. It's been done by our physicists, and it's also been done formally by Accenture, so I'm happy that these results in the non-target organs are absolutely 100% correct.
The kidney dose is 0.28 gray per GBq, sorry, compared to 0.58 and 0.71. When you look in the lacrimal and salivary gland, you've got significantly lower lacrimal and salivary gland activity than either PSMA-617 or PSMA-I&T, but we don't have lower tumoral activity. That's a really nice combination. Low salivary, low kidney, maintained tumor, and that's really what you wanna see. Next slide. When we look here, we've got on the left, we've got the four-hour, 24-hour, and 120-hour delayed imaging SPECT/CT after a single dose of lutetium-PSMA-597, 7.5 GBq. Four-hour image, you can see a lot of background activity. You can see some low-grade salivary gland activity, not very bright.
Really almost struggle to see the kidneys, quite nice bright tumoral activity. 24 hours later, tumoral activity looks a bit brighter. Salivary gland activity looks a bit less bright. Once again, struggling to see the kidneys 'cause there's quite a lot of bowel excretion with this agent. 120 hours, really nice bright tumor. Almost can't see the salivary glands at all and definitely can't see the kidneys. On your right is similar time points. We're comparing this to PSMA-617 SPECT dosimetry. You can see those salivary glands are really quite bright, and they stay bright up to 160 hours following injection. Similarly with the kidneys, you can see quite bright activity within the kidneys, staying bright up to 168 hours post-injection. I do think that this is a very nice dosimetry.
David, I actually think this is OPTIMAL-.
Yeah
dosimetry for a small molecule, right?
Well, I think, Professor Emmett, it'd be really, really interesting to sort of hear a little bit more about what prompted your. I mean, this is very intellectual thinking. You know, what you've set out to do in this study is one singular question you're aiming to answer, which is does dose intensification, which is really the concertinaing together of the first three fractions. You're dosing day one, day three , day 15 very intensively. The underlying thesis that you formed in designing this trial was the upregulation of the PSMA target. Maybe you could talk about the data on that, the literature on that, and why you thought that this approach might work.
Actually it's the upregulation of the PSMA receptor with DNA damage is an appealing concept, and there's some preclinical work on that and some work we did at St Vincent's. The other thing is, you know, we got the radiobiologists tell us that when we hit with lutetium, it's all done and dusted within a couple of days. There's some very nice work in lymphocytes that show that you have radiation-induced foci for up to about 96 hours, but after that.
Mm-hmm
it's all healed. DNA damage repair heals it all. Two things. What I'm really interested in is if we instead of just giving one big dose up front, we split it up, and we give it in a timed fashion to when the DNA damage is not yet healed, do we get a deeper hit by hitting already damaged cells? That's one thing. Johann de Bono's lab, she and et al a couple of years ago published this very nice work that if you damage the cell, prostate cancer cell, particularly mCRPC prostate cancer cells with radiation, you actually increase PSMA expression. That happens in the first few days as well. We actually explored that last year.
We presented at the PSMA Theranostics Conference a series of patients where we did day one, day seven dosing with lutetium PSMA-I&T.
Mm-hmm.
2/3 of those patients actually had increased PSMA expression. Putting the wanting to hit while the cell is damaged together with wanting to have increased PSMA expression, we came up with a day one, day three dosing. We thought, Scott Tagawa's got some great outcome data with day one, day fifteen. We did day one, day three, and then day fifteen. Obviously that's a brave trial to be doing 'cause we would clearly be concerned about toxicity, so we have done a series of data safety monitoring board meetings within the trial to see, you know, whether we ran into toxicity at all. The idea is if we can intensify dosing and time it to the radiobiology and the PSMA biology, can we actually get really, really deep responses in these patients?
next slide.
Understood. Mm-hmm.
This is actually the trial schema. It's a randomized phase II as you said. It's a two to one dosing. We've got 80 patients in the dose-intensified arm. We've got 40 patients in the standard of care arm. Patients had to have metastatic castration-resistant prostate cancer. They have to have failed an ARPI. They have to have failed docetaxel or be chemo-ineligible for docetaxel, but a lot of patients on this trial have actually failed one or two lines of chemotherapy. They have quite high volume disease. And then in the first 35, 40 patients on the trial, we actually started at 7.5 GBq in the dose-intensified arm. We gave 7.5 GBq day one, day three, and day 15, and then ten weekly in the experimental arm.
In the standard of care arm, it's 7.5 GBq six doses, six weekly until no longer clinically benefiting, which is essentially standard of care.
Yeah.
All patients have a PSMA PET scan.
Mm-hmm.
We started off using the VISION criteria with the PSMA PET scan. We actually moved to the NTP criteria after the first data safety monitoring board meeting, we do a repeat PET at eight weeks on all patients in the trial.
Professor Emmett, are these patients, given your referral patterns from both metropolitan Sydney and regional centers, what is the patient population? What prior treatments have they been exposed to, you know, given that it's Sydney, Australia?
It's a mix.
Yeah.
It's a mix. The vast majority.
Mm-hmm
... of patients have had docetaxel. A significant proportion of patients have had both docetaxel and cabazitaxel. All patients have received at least one androgen receptor pathway inhibitor. All patients are metastatic castration-resistant. I think we have a very high volume of disease on the trial. Because we don't have much access in Australia to Lutetium-177 PSMA therapy at the moment, we've deliberately made the inclusion criteria to this trial very broad. We take very sick patients.
Yeah.
Um-
Understood.
We take super scans. We take patients who are hemoglobins of 80 and falling, and we get these patients onto this trial. The primary endpoint, because we're looking about whether we can go deeper, whether we're going to be deeper in terms of our responses with dose intensified, the primary endpoint is PSA 90% response rate. I think that's quite a high bar in terms of primary endpoint. We're also looking at PSA 50% response rate, PSA and radiographic progression-free survival, overall survival. Importantly, safety, quality of life, and dosimetry. We're doing multi-time point dosimetry in all the patients on the trial on both arms so that we get very good data about lutetium-PSMA-597. We're going to be able to look at biologic effective dose of dose-intensified dosing compared to standard of care dosing.
We're also doing ctDNA on this. We're doing ctDNA at multiple time points, so we can look at ctDNA clearance. Are we actually clearing cancer cells from the blood using a more intensified dosing than we are with the standard of care dosing?
Mm-hmm.
Because lutetium-PSMA-597 is so new, the standard of care gives us a great opportunity just to see how it benchmarks compared to other lutetium PSMA agents, small molecules, and antibodies.
Yeah, look.
In terms of toxicity and effect.
I think an obvious question is, given the extent of prior treatment that these patients in this trial have received, how are they in your experience so far, and you've I know you've recruited very rapidly, how are they tolerating that dose-intensified regimen in the experimental arm? Could you comment on that?
Yeah. You know, it's one of those things everyone thinks you're very brave and looks at you slightly askance that we're even thinking about doing this dose regimen. When I first put the patients on the trial, I told them they may need blood transfusions, they were gonna feel terrible, they were gonna have this, they were gonna have that. You know, it's been very interesting in terms of the toxicity. The toxicity has been very low. We did the data safety monitoring board meeting with the 8.5 GBq dose-intensified in March. We looked at the first ten patients who had dose-intensified lutetium-PSMA-597, and that was after ten weeks. I think we had five grade 1, so we had five grade 1 anemias. We had two grade 1 thrombocythemias.
We had one patient who had grade one xerostomia and two grade three lymphopenias.
Mm-hmm.
You know, it is well-tolerated. I will say that with the dose intensification in patients who have very high volume disease, we do make pain worse in the first couple of weeks. You know, they get a really big response to this dose intensification in their, at their sites of disease. We do have to make sure they have a pain plan, and we do put them on dexamethasone for the first couple of weeks just to reduce the fatigue that they might feel as well.
Mm-hmm.
That's actually a treatment response effect.
Mm-hmm.
You know, get a bit of pain around the time of Lutetium-177, that's a good sign. No pain is not a good sign. Their pain's great. They're coming off their opiates. They're feeling very good.
Mm-hmm.
You know, what I really want from this. They're great. We're not having any problems on this trial, but what I really wanna know is can we make it last longer as well?
Yeah. Yeah. Understood.
Next slide. This is just a couple of the early patients, and it's one of the things that just showing what's happening between the day one and the day three dosing in these patients, and it's pretty uniform. When we give the first injection, you can see here, it says dose one, day one. On the far left, the SUVmax of the salivary gland was 11, SUVmean 9.4 of the tumor, and this patient's got metastatic disease in bone in their mid-thoracic spine, and they've got a series of lymph nodes in their para-aortic region that you can see there. If you go to dose two, day three, this is the SPECT images taken after the second injection, day three. You can see the salivary gland looks a lot less bright. Right?
It's gone, not as bright, and the SUVmax is five. The tumoral intensity is actually gone up. The SUVmean in the tumor has gone up to 14. The SUVmax has gone from 51 up to 124. We're getting increasing intensity in the tumor, and we're getting reduced intensity in the salivary glands, and if you look at the next patient, you can see the same thing. Salivary gland activity, dose one, day one, SUVmax 5.2. Dose two, day three, it's gone down to 1.8. You almost can't see it at all. It's super interesting, this, that you are reducing salivary gland activity while increasing tumoral activity. In this second patient with very high volume disease, you can see the SUVmean has gone from 5.7 to 7.9.
SUVmax gone from 25 to 74, and the tumoral volume's gone from 2,379 mils to 3,977 mils. Whatever the mechanism, we're getting a lot more Lutetium-177 into those cells with the day three dosing.
Yeah.
The question is whether we're getting more dose into those cells than we would dosing them week one, week six.
Mm-hmm.
That's one of the big questions of the trial, really.
Would you say that, I mean, this is, I don't know if you can answer this question, but would you say that there is a correlation between the low radiation dose imparted to the normal tissues that you don't want to hit and the tolerability safety profile of what you've seen? Can you not draw that conclusion yet?
I think so. I mean, I don't think, you know, we'll do all 120 patients and draw that conclusion.
Yeah.
We're giving 25.5 GBq in two weeks.
Mm-hmm.
In that data safety monitoring board meeting, we had one patient with grade 1 xerostomia. I'm super happy with that. I don't know whether that's 'cause we're saturating. There's a different mechanism of uptake in salivary glands to tumor. We know that. It looks to me like this dosing regimen is saturating the salivary glands, but it's not saturating the tumoral activity day one, day three. We know if we gave cold PSMA and then gave an injection of Lutetium-177 PSMA, we would have reduction in salivary glands, and we'd also have reduction in tumor. Perhaps the regeneration of the PSMA expression in tumor is so fast that we've still got saturation in salivary glands in day three, but we've actually overcome the saturation that we might have had.
Yeah
... with the, injection day by day three in the tumor, and we've got increased.
Yeah
Expression either in relation to DNA damage or because we're overlying dose and we've got persistent activity 'cause this agent has got really nice persistence in the tumor cell. Either way, I don't care. It's looking really bright. I can see we're getting a really nice deep radiation dose to all of those sites of disease where we want it, and we're not getting it where we don't want it.
Mm-hmm.
I'm happy with that. That's cool. Those images are really cool for me.
I like the images too. Yeah. Thank you. Thanks, Professor.
Next slide. This is just one of the patients on the study, and these are four-hour SPECT images, they're actually underestimating the volume of disease of these patients. This is a patient who's pretty classic for us post-chemotherapy, post two-lines, obviously post-ARPI because that's an inclusion criteria, very high volume disease. PSA is 101,380, hemoglobin 112, platelets 200. What we have here is the day one, day three, day 15 dosing, and these are the SPECT/CT images that are all taken four hours after each injection, and then we have the week 10 dosing. You can see that in this patient, the day one dosing, high volume disease. Day three, it looks, you know, the volume has gone up again.
Day 15, you get the impression it's not as bright. There's things going down. By week 10, there's a marked reduction in the number of sites involved, so a marked reduction in the volume. You can see PSA's gone from 1,380. Day three, it's actually gone up. That's something that we routinely see. Pretty mixed at day 15. Sometimes it's up, sometimes it's down to 40 by week 10. Really nice PSA response there correlating with the really nice SPECT imaging response that we see at the week 10 dosing. Very nicely, the hemoglobin is maintaining itself. The platelets are maintaining themselves. We're not getting a lot of, we're not getting extreme hematotoxicity at all in these patients.
It'll be interesting, I'll ask you at the end, but your view as you go through, your view on where the behavior of this peptide, small molecule, lends itself to future development, 'cause you're gonna touch on that with earlier use.
Yeah
Back to you. Yeah.
Next slide. I think we're almost there. I mean, I. The OPTIMAL-PSMA trial is a randomized phase II. We're at, I think we're randomized. I think we randomized the 90th patient today out of 120. We are getting another site on board, but that's essentially 90 patients at a single site, at St Vincent's Hospital Sydney diagnostics department in Sydney. As you were saying, David, a lot of these patients are rural. They come from all over the place to receive this treatment, so it's wonderful that we've been able to help them with this trial and that they've tolerated it well enough. A lot of patients are getting to the end of treatment, so they're getting all six doses, which is also fantastic.
The median number of doses in therapy was four, and that's because patients progressed around that time. About 45% of patients had progressed by dose three in the therapy trial. To me, that's the thing to beat, keep them on trial longer, and see how long we can keep them on trial, how long we can keep them alive and feeling well.
Yeah. Yeah. Well, as I talked about earlier in the intro, you know, Professor, Dr. Azad, you know, a colleague of yours, you know, from across the border in Victoria down in Peter Mac, made that very thoughtful discussant session of PSMAddition, and talked about some of the requirements for an agent for, you know, metastatic hormone-sensitive prostate cancer. I think it'd be very interesting to get your thoughts on, you know, the development, you know, in that disease setting and your OPTIMAL-E trial that you've already, I think got, IRB approval for.
We do. You know, I think, one of the reasons why we had the baseline PSMA PET and then the week 8 PSMA PET was we're thinking with the intensified dosing, we might be able to stop treatment in some of these patients. We do treatment pauses frequently. They continue the ADT, but they pause treatment with Lutetium-177 PSMA.
Mm-hmm
Until they get first confirmed rise in those patients who have a marked reduction in PSA and volume on their SPECT or their PET images. We've had very high-grade aggressive disease in the patients here. A number of these patients are actually super scans. We've had good deep responses, I believe. We haven't paused treatment in any of the patients in mCRPC. I think in mHSPC, you have much better behaved clonal populations. You have more sensitive disease. It's a combination. It's always combinations that you use. At PSMAddition is ARPI, androgen receptor pathway inhibitors plus ADT plus lutetium PSMA. We showed in the ENZA-p trial that if you use two effective agents together, your responses are massively deep.
Our PSA 90% response rate in mCRPC in ENZA-p was 95%. You know, if you're using ARPI + ADT + lutetium very early, you're gonna get extremely deep responses, and a lot of patients will have no disease left. If you just keep treating them, then you're gonna end up getting a higher dose to the non-target organs. I think lutetium-PSMA-597 does lend itself well to the earlier space. It's got low salivary gland, low kidney activity. We haven't seen a lot of hematotoxicity yet, though of course, we have to read out the whole of OPTIMAL-PSMA. It does lend itself to going earlier. I think it also, this idea of adaptive dosing in the hormone-sensitive space where you treat up front, then if you lose the target, you stop.
You continue the very active ARPI and ADT regimen, and then at first confirmed PSI, PSA, you retreat again. Next slide. I think we've got the OPTIMAL-
Ah.
E concept.
OPTIMAL-E.
This is OPTIMAL-E. This is the version of OPTIMAL-PSMA, except it's in the metastatic hormone-sensitive space, so patients who've got metastatic disease at diagnosis. You can tell it's designed by a nuclear medicine physician because it's stuffed full of imaging. And we really want to see what's happening to that target as we go. There's a screening PSMA PET to make sure they've actually got disease. And then we, the patient goes on ARPI, so an androgen receptor pathway inhibitor, either enzalutamide or abiraterone or darolutamide, and then at day eight after commencing the ARPI, they have a PSMA PET. And then we commence day one and day three, so we do a dose intensification, 8.5 GBq of those patients on the trial. We do a six-week dose.
We do a 12-week PET. If there is no residual disease on the 12-week PET, with the Lutetium-177 PSMA, ARPI, and ADT on board, we stop the Lutetium-177 PSMA-597. ARPI and ADT would continue until first confirmed PSA rise. We would start administering again. If there is residual disease, then we give another two doses of Lutetium-177 PSMA-597 at week 14 and week 22 when the patient has another opportunity at six months, so week 24, to see whether all disease has gone on the SPECT as well as the PSA, sorry on the PET as well as the PSA, and if it hasn't, they get another two doses. This is what we call adaptive dosing.
Mm-hmm.
We're trying to treat when the target is present, stop if it's not present, and then recommence again the minute target starts to come back. We look at target coming back based on PSA rise. The question is how long can we go?
Mm.
In some of these patients with very well-behaved disease with a dose intensification up front with the Lutetium-177 PSMA and then stopping if they've got well-behaved disease, is it years? I hope, I really hope that that's years before that clonal population comes back. In the NeCAP trial, which we did a similar thing, we did a PSMA PET so that we could start and stop treatment. You know, some of those patients only got two doses, and it's six years now, and they still have no measurable disease.
Mm-hmm.
Can we treat multi-clonally, and actually eliminate whole clonal populations for these patients? Potentially a cure.
In your mind, what would you want to see? Obviously, OPTIMAL-E in metastatic hormone-sensitive prostate cancer is really the first proof of concept with dose intensification and dose adaptation so that we don't over-treat blindly, you know, a patient and, you know, negatively impact their quality of life. What would you wanna see from such a study if you were to say, "Right, based on achieving this outcome, this warrants, you know, a registration-enabling, you know, pivotal trial in this early disease setting"?
I hope we get a number of patients with reasonably high volume M1 disease in this small study. I hope that we see that the ARPI and the ADT and the Lutetium-177 PSMA are working extremely well together with the dose intensification such that when we get to week 12, 3 months, I'm hoping we have a very high proportion of patients who have a PSA of less than 0.2 and nothing left on the PSMA PET. A lot of the benchmarks for overall survival in MHSPC is around the week 24 mark with a PSA of less than 0.2. What proportion of patients can we get to that?
If you're just ARPI and ADT, and you are using, and you're not using Lutetium-177 PSMA, that's about 68% of patients you would expect to have a PSA of less than 0.2 at six months. What proportion can we get to without inducing a lot of toxicity just by dose intensifying up front and then giving patients an opportunity to de-intensify their treatment and go back to the ARPI and the ADT again? How does our quality of life compare, say to, six doses up front? There are other trials that are doing this. SAMPP's got a very
Mm.
Interesting design. It's using, it's giving baseline, it's giving day one, day 7.4 GBq of Lutetium-177 PSMA-617 with ARPI and ADT. Then six weeks later, it's giving day one, day seven again. Six weeks after that, it's giving another day one, day seven. I think they're beyond the window of the DNA damage. They don't have the adaptive dosing design. I think the adaptive dosing design is something that patients want.
Yeah.
They will want that.
Mm-hmm.
I do want to know whether it works. Certainly in the studies that we've done in the castrate-resistant setting, we've seen no disadvantage to stopping treatment with losing the PSMA target. Patients feel well. They're not coming in for continued treatment. They don't have the associated toxicity. They don't get the very dry mouth. Potentially, we're avoiding renal toxicity, then we're treating when they really need it, when the PSA starts to rise again and the clone is on the move.
Yeah. Yeah. That's very clear. Mm-hmm.
I think it's interesting we've got different ways of doing it, but if we got to week 24, all of our patients had a PSA of less than 0.2 or 95% of them had a PSA of less than 0.2, and 70% of them had been able to stop treatment, because they didn't have anything left on their PSMA PET. I think that'd be amazing.
Yeah. You're saying that would be your benchmark for saying, "Right, it's pivotal trial time." Yeah, understood.
Well, that's my benchmark. Obviously, other people will have different benchmarks.
Yeah.
I would be pretty happy with that.
Yeah. Yeah. Yeah. Very clear. Very clear. Okay.
Just wanna say one thing, David, that is, you know, we were so grateful to do this trial. OPTIMAL-PSMA has provided treatment access to many men across New South Wales in Australia. They are very grateful. I'm grateful that Telix has provided this access to this drug. It's been fantastic. I just wanna shout out to my team. Putting 90 patients on as a single site with a randomized phase II trial has been heroic, I really wanna say thank you to them.
No, I think, I think, Louise Emmett, that's a critically important point. I've never seen, a single center trial, enroll at the rate that you've been able to do. You and team and your patients are truly something, out of the ordinary. Thank you.
Next slide.
Okay. Look, on behalf of those who have dialed in to the webinar, I'd really like to thank Professor Emmett, who's, I think, evidently doing some of the most evolved thinking in prostate theranostics at the current time. These are the concepts that take a lot of CPU cycles in an academic's brain. I think, you know, we're seeing that a lot of thinking's going into this, Professor Emmett.
I hope today's discussion has gone some way to look, clearly articulating Telix's portfolio approach based on two very distinct mechanisms of action, TLX591-Tx in metastatic castration-resistant prostate cancer, but now, TLX597-Tx, you know, which is exhibiting some best-in-class small molecule distribution and dosimetry and tolerability characteristics that we believe make it really uniquely suitable for achieving the requirements for metastatic hormone-sensitive prostate cancer that was so well articulated at ESMO last year, i.e., that the goal of any anti-cancer treatment is to make patients live longer and live better. One without the other is not sufficient.
I.e., two, that to deliver the best outcome in metastatic hormone-sensitive prostate cancer, it's gonna take a really patient-centered approach, which Professor Emmett's really, I think, driven home, about not over-treating and adaptive dosing, you know, focused on avoiding over-treatment, focused on minimizing the impact on quality of life, and focused on minimizing late toxicities. With that, I'd like to thank you. I'll pass back to the operator. We'd be very happy to take any questions from the audience.
Thank you. If you would like to ask a question via the phone, you'll need to press the star key followed by one on your telephone keypad. If you would like to cancel your request, please press star two. If you are on a speakerphone, please pick up the handset to ask your question. Your first question today comes from David Dai from UBS. Please go ahead.
Great. Thanks for taking my questions. Just on the safety, it looks like dosimetry to bone marrow is correlated to tumor lesion, where the patients without extensive bone lesions have limited dosimetry to bone marrow. Based on this data, how should we think about the potential hematological toxicity for TLX597-Tx, especially in early-line hormone-sensitive prostate cancer patients?
Yeah. Thanks, David. Great question. I think, as you've seen, Professor Emmett presented the preliminary dosimetry, and she was at pains to explain that that was in the first 12 patients that were enrolled to the trial. Ongoing dosimetry work's being done. It's very clear that the dosimetry it's a multiple in of PSMA-617. It's a multiple of that agent in the tumor lesions, and it's a percentage or it's a fraction of relative to that agent in the non-tumor compartment. That's the salivary glands, that's the kidneys, and that's the bone marrow. Professor Emmett has not extensively reported on the bone marrow dose, but it is similar to the kidney and salivary glands, very low.
That's why the hematological toxicity, you know, with small molecules as a class of drugs, but in particular with this second-generation agent. The bone marrow dose is also very, very low, and that's what's correlating with the low clinical expression of hematological toxicity. It's very, it's a very consistent profile, David, across the tumor compartment and the non-target normal tissue compartment, whether it's salivary gland, kidney or bone marrow. Does that, does that answer the question?
Yeah, that's really helpful. Let me just kind of follow on under dosimetry. I just wanna kind of hone in a little bit more. You know, just based on the SPECT biodistribution data, it looks like there's some dosimetry in GI. Maybe just talk a little more around, you know, what do you think a potential GI tox looks like, especially the constipation or diarrhea and vomiting that we're seeing for Pluvicto. Do you expect this to be replicated in 597 as well?
Well, we don't, no. The reason we don't is that, you know, we are developing, just to be clear, we're developing a new radiopharmaceutical. It is not in any way a generic version of Pluvicto. It's a new structure to it. It's basically been designed with a different linkage to Pluvicto and PSMA I&T and the other small molecule agents that fundamentally alters its chemical and its physiological properties. Unfortunately, I can't really disclose more than that. Those altered chemical and physiological properties govern its biodistribution, which is essentially where it goes, and ultimately where it goes governs the dosimetry, you know, the radiation absorbed dose that it physically imparts.
All of the off-target or off-tumor tissues are touched by this asset very, very minimally, and that includes the GI tract as well. The adverse event profile that Professor Emmett has observed in her 90 patients that she reports to her independent data monitoring committee have had very low constitutional side effects, you know, fatigue, nausea, vomiting, relative to the other small molecules.
Got it. That's really helpful. Thank you so much, David.
Pleasure, David.
Thank you. Your next question comes from Andy Hsieh from William Blair. Please go ahead.
Thanks for taking my question, and thanks for answering a very important, perhaps, long-overdue clinical question about dose intensity and optimization. I have a question about the patient enrollment criteria. I think for the OPTIMAL-PSMA, the enrollment criteria was VISION and then transitioned to more ENZA-p. Maybe for the first part, I am wondering if you could talk about why ENZA-p enrollment criteria is enriching patients who will be likely candidates for intensification. Also the rationale for the OPTIMAL-E. It seems like it went back to the VISION study, maybe kind of the rationale behind, you know, that enrollment criteria. Maybe a quick one.
Yeah.
For docetaxel... Sorry, not docetaxel. For dexamethasone usage, I believe that dexamethasone also reduces PSA. I guess when you look at the PSA reduction down the road, I'm curious how you would interpret the data delineating between, you know, the 597 contribution and also the dexamethasone contribution. Thank you.
Yeah, Andy, basically, characteristically solid question from you. The first question, just to restate it, is you asked about in Professor Emmett's current on-foot OPTIMAL-PSMA trial, which is enrolling 120 patients is the target, and she's done. She's enrolled 90 of the 120. During the trial, she increased the PSMA positivity criteria, where she started with the VISION criteria, and she tightened the criteria to the ENZA-p criteria, which is a study that she was the principal investigator on.
The primary reason she did that was that these patients in Australia are very late-stage, so metastatic castration-resistant prostate cancer, very heavily pretreated, and they have failed or progressed while on or become intolerant to all of the conventional therapies, which is primarily ARPI and taxane chemotherapy, mostly cabazitaxel and docetaxel. These patients are very heavily pretreated. What Professor Emmett wanted to do was to evaluate in this trial. She started with a dose-intensified regimen. She wanted to further dose intensify, which she did during the trial with the permission of her IRB. She went from 7.5 to 8.5 GBq. She's now injecting a much higher amount of activity at each injection.
She's concertinaing the first three injections together, if you will, on day one, day three, day 15. That's a very dose-intensified regimen. What she wanted to do was make sure that with that heavily dose-intensified regimen and in the population of, excuse me, heavily pretreated patients, that she was making sure that they were highly PSMA positive before they were enrolled, you know, as a means of making sure that they were appropriate patients. That's why she's done that. In terms of what this OPTIMAL-PSMA trial has shown, it has shown that this molecule is, it really facilitates three objectives. Number one is dose intensification and dose adaptation, which is only, you know, treating when the target is present and not over-treating when it's not present.
Number two, this has shown that the off-target deposition in the normal tissues uniquely lends itself to the metastatic hormone-sensitive prostate cancer setting, which is what this trial OPTIMAL-E will evaluate. Thirdly, if you think more over the horizon, it lends itself to use with an alpha isotope, again, because of the low deposition in the kidney in particular. That's why Professor Emmett has already planned and got approval for OPTIMAL-E, which is the study she talked about, phase II trial in 20 patients that is combining this agent with conventional androgen deprivation therapy and ARPI. I can't really comment on really the role of concurrent steroid. She will look at the four ARPIs.
She'll start with darolutamide and enzalutamide and then expand this trial to apalutamide and abiraterone. All four will be studied, and then we'll be able to answer that question once those data are in hand. It's a detailed answer to a very thoughtful, detailed question, but I hope that addresses it, Andy.
Absolutely. Thank you so much.
My pleasure. I think we've got time for a couple more questions. We've got about two or three minutes to go.
Thank you. Your next question comes from Melissa Benson from Barrenjoey. Please go ahead.
Morning, David. Thanks for taking my question. I just wanted to kind of step back and understand, I guess, the rationale a little bit more about the two-product strategy. If it is kind of focused, and it seems like it's based on this, you know, reduced delivery uptake, low renal clearance. Those are kind of both attributes of TLX591-Tx, obviously, because of its-
Mm-hmm.
-antibody nature. Trying to understand, is it perhaps that the hem tox profile is less acceptable in earlier stage hormone-sensitive disease, and that's part of the rationale? Is there anything that I remember you had the ProstACT TARGET trial with TLX591-Tx, which was in that earlier BCR setting, but some of those patients are effectively hormone sensitive. Is there anything you learned in that that's guided this need for a two-product bifurcation? Thanks.
Thanks, Melissa. I think that's an important question, but it warrants a, you know, a thoughtful answer. I think the key point is that we at Telix are fundamentally focused on the patient, and a focus on the patient requires a focus across the entire disease journey or spectrum. You can see that in the prior compositions of the therapeutic portfolio for prostate cancer, it includes TLX591-Tx, but it also includes the development of TLX592-Tx, which is actinium, you know, an alpha therapy, which must follow lutetium. It can't go ahead of lutetium.
After alpha, an agent for bone pain, which is a sort of a pre-palliative stage of the disease journey. We have, you know, we continue to develop TLX591-Tx. It's uniquely positioned as a radio antibody-drug conjugate for metastatic castration-resistant prostate cancer. I think we've espoused its unique virtues, you know, in a very detailed kind of way. It's, you know, the long tumor retention, the prolonged radiation dose deposition, and the fact that it is able to be given as a two-fraction, two-week apart dosing regimen really lends itself to be intercalated or combined with conventional standard of care that a patient is going to get. We're asking the question, can we layer on top of standard of care, a radio antibody-drug conjugate?
From there, though, we have looked upstream to mHSPC, and we have really thought deeply about the findings of PSMAddition. We have been thinking about this for a long time. We don't believe that just treating blindly, you know, with six fractions, when the target might disappear is in the best interest of the patient. We believe that in that early disease setting, a mandatory precondition is that you do not do two things. You cannot adversely affect the patient's quality of life by having significant off-target effects. Secondly, you cannot injure critical organs like the kidney and have long-term toxicities because these patients, we are aiming to help them live a long time, measured in years.
We cannot be allowing them to live for years, but it with, you know, renal injury and potentially, you know, renal dialysis as a consequence. That's why it requires a very patient-centric approach. A fundamental rule in medicine is to do no harm. You know, first of all, do no harm. That's why we think an asset like this is intended for metastatic hormone-sensitive prostate cancer in that early metastatic setting. That's what I would want if I was a patient. Melissa, I hope that makes sense. That's our view of the world, and I think it's a very thoughtful view of the world.
I think, you know, you can hear the sort of ambition that Professor Emmett has in taking this upstream to where she's currently studying it.
Thanks.
My pleasure. I hope that answers the question. I think we're probably at time. I just apologize if there's any other questions that we haven't been able to get to. We would be very happy to have those triaged to our industrial relations team. Louise Emmett was at pains to say she'd be delighted to respond to any questions. It's 2:00 A.M. in Europe at the moment, we can't ask her to do it right now, of course, within sort of the next day or two, she'll be very keen to respond. I'll hand back to the operator with that. Thank you to the audience for dialing in, thanks for your attention.
Thank you. That does conclude our conference for today. Thank you for participating.